By definition, vitamin D is not a true vitamin since adequate exposure to sunlight either negates or significantly diminishes the need for dietary supplementation. Instead, this imprecise descriptor refers to a group of steroid molecules also encompassing both vitamin D2 (derived from plants that utilize ergosterol rather than cholesterol) and vitamin D3 molecules (derived from cholesterol). The human body thus procures vitamin D through two independent pathways: the photochemical action of solar UVB light (≈ 295 to 320 nm) in the skin and some limited dietary sources (1
Given that vitamin D2 is produced by plants, dietary sources (naturally occurring and/or obtained via oral supplementation) are the only means for acquiring it. Vitamin D3, on the other hand, is predominantly procured via the sunlight driven cutaneous reaction described above or from dietary sources. For adults, consumption of fatty fish and/or oral supplementation supplies the most abundant amounts of vitamin D3. In contrast, the major dietary sources of vitamin D in the pediatric population are provided by fortified foods such as cereal, cheese, and milk, none of which are uniformly consumed in large quantities by all age groups. The average adult diet typically provides less than 10-20% of an individual’s vitamin D stores with a child’s diet likely to provide even less vitamin D (2
In the body, 25D (25-hydroxy vitamin D) is the major circulating vitamin D metabolite. It is generated predominantly through hepatic 25-hydroxylation via many potential catalysts, including CYP2R1 and CYP27A1. The conversion to hormonal 1,25D (1,25-dihydroxyvitamin D) requires the enzyme CYP27B1. The kidneys have long been considered the major site for 1α-hydroxylation of 25D to 1,25D. Unlike the loosely regulated hepatic hydroxylation of 25D, the renal 1α-hydroxylation falls under tight control of PTH (parathyroid hormone) and is primarily involved in calcium regulation and signaling. In sites other than the renal tubule (keratinocytes (3
), the trophoblastic layer of the placenta (4
), IFN-γ stimulated macrophages (5
), and granulomata (6
), this type of fastidious regulation is either absent or operates very inefficiently. Compared to adults, strict control of renal 1α-hydroxylation and the normal feedback suppression by 1,25D is also less precise in infants.
Once converted, 1,25D serves as the active form of vitamin D and binds to the VDR (vitamin D receptor), a nuclear receptor and ligand-activated transcription factor (7
). VDR is expressed in most tissues and regulates cellular differentiation and function in many cell types. For example, VDR expression is found in monocytes as well as stimulated macrophages, dendritic cells, NK cells, T cells and B cells of the immune system. Activation of the VDR leads to production of downstream gene products. In immune cells, VDR activation elicits potent anti-proliferative, pro-differentiative, and immunomodulatory effects.
Initially, research focused on the role of vitamin D in bone metabolism and calcium homeostasis. Regulation of intestinal calcium transport is still the most significant effect of 1,25D acting through its binding to the VDR. More recently, however, it has become clear that vitamin D has pleiotropic effects, including some VDR transcription-independent actions and plays a key role in immune system regulation. Activation of the VDR by 1,25D, the active form of vitamin D alters cytokine secretion patterns, suppresses effector T cell activation and induces regulatory T cells. In dendritic cells, it has also been demonstrated to affect maturation, differentiation and migration. 1,25D can enhance the phagocytic activity of macrophages and increase the activity of natural killer cells. Therefore, tissue and cell-specific differences in the regulation of 25D are highly relevant to the roles of 25D and 1,25D as immunomodulators.
The effects observed with vitamin D are dependent on the availability of the substrate. Designations for sufficient, toxic, insufficient and deficient states are defined by the serum concentrations of 25D. Normal 25D concentrations associated with a vitamin D sufficient individual are usually greater than 30 to 32 ng/mL (75-80 nM). Hypervitaminosis D is arbitrarily defined as 25D concentrations > 100 ng/mL (250 nmol/L). However, people living and/or working in sun-enriched environments, such as lifeguards and sunbathers, reached 25D concentrations exceeding this value without evidence of deleterious consequences beyond the well characterized solar damage from UVR (ultra violet radiation) (8
). Symptoms of vitamin D intoxication typically do not manifest until circulating 25D concentrations rise above 150 ng/mL (375 nM). The most common adverse effect is hypercalcemia, which can lead to the formation of kidney or bladder stones and cause renal failure.
Vitamin D deficiency is typically defined as circulating 25D concentrations less than 20 ng/mL (50 nM) (7
). In this state, the subsequently low ionized calcium concentration stimulates PTH secretion, which eventually leads to increased 1,25D synthesis. The elevated PTH concentrations also lead to a decrease in bone mineralization and osteomalacia. In the immature bones of children, the term rickets describes the osteomalacia and the abnormal organization of the cartilaginous growth plate along with the accompanying impairment of cartilage mineralization (10
). PTH and 25D concentrations are inversely related until the 25D concentration is greater than 30-40 ng/mL (75-100 nM), after which PTH concentrations fall precipitously.
Individuals with 25D concentrations > 20 ng/mL (50 nM) have been originally classified in the vitamin D sufficient category. With more information emphasizing the important roles vitamin D plays outside of calcium homeostasis and bone metabolism, 25D concentrations that span the range between the loosely defined parameters of vitamin D sufficiency and deficiency are now associated with manifestations of disease. In both the adult and pediatric population, use of the term vitamin D insufficiency is increasingly recommended for ranges that fall between 20 ng/mL (50 nM) and 30 to 32 ng/mL (75-80 nM) to account for these observations.
During the winter solstice period (outside the latitudinal lines, Tropic of Cancer and Tropic of Capricorn), surface solar UVB irradiation is inadequate to trigger sufficient production of vitamin D3. The seasonal variations in temperate climates, related to distance in latitude from the equator and decreased sun exposure, greatly exacerbate the problem of vitamin D insufficiency/deficiency. The melanin content in the epidermis of an individual also affects absorption of UVB with darker pigmented individuals absorbing less UVB due to melanin acting as a natural sunscreen. Any mechanism that prevents UVB absorption (clothing, increased pollution, longer periods spent indoors, etc.) works in a similar fashion to prevent cutaneous production of vitamin D3. Using the definitions from above, estimates suggest that 1 billion people around the world may be vitamin D insufficient/deficient.
In characterizing the global health status of children, recognition of vitamin D insufficiency has increased significantly, particularly over the past 20 years. In the United States, relatively high rates of vitamin D deficiency not necessarily associated with rickets have been reported in healthy infants (11
), children (13
) and adolescents (15
). A high prevalence of vitamin D deficiency has also been reported in infants, children, and adolescents from other countries, including the United Kingdom (17
), Greece (18
), Lebanon (19
), China (20
), Finland (21
), and Canada (22
). Besides the resurgence of rickets, vitamin D insufficiency in children is implicated as a risk factor for the development of chronic diseases later in life, including asthma, diabetes, heart disease and cancer (23
). A separate study from the United Kingdom also found that the cost of preventing vitamin D deficiency in a high risk population of Asian children theoretically favored this approach as compared to the financial burden of treating the general health problems associated with chronic vitamin D deficiency (24
). Despite the small cohort, the study provides an impetus for considering more aggressive prevention and treatment of widespread vitamin D deficiency.